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Spatial encoding of cyclic AMP signalling specificity by GPCR endocytosis
G protein-coupled receptors (GPCRs) are well known to signal via cyclic AMP (cAMP) production at the plasma membrane, but it is now clear that various GPCRs also signal after internalization. Apart from its temporal impact through prolonging the cellular response, does the endosome-initiated signal...
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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2014
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232470/ https://www.ncbi.nlm.nih.gov/pubmed/25362359 http://dx.doi.org/10.1038/nchembio.1665 |
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author | Tsvetanova, Nikoleta G. von Zastrow, Mark |
author_facet | Tsvetanova, Nikoleta G. von Zastrow, Mark |
author_sort | Tsvetanova, Nikoleta G. |
collection | PubMed |
description | G protein-coupled receptors (GPCRs) are well known to signal via cyclic AMP (cAMP) production at the plasma membrane, but it is now clear that various GPCRs also signal after internalization. Apart from its temporal impact through prolonging the cellular response, does the endosome-initiated signal encode any discrete spatial information? Using the beta2-adrenoceptor (β2-AR) as a model, we show that endocytosis is required for the full repertoire of downstream cAMP-dependent transcriptional control. Next, we describe an orthogonal optogenetic approach to definitively establish that the location of cAMP production is indeed the critical variable determining the transcriptional response. Finally, our results suggest that this spatial encoding scheme helps cells functionally discriminate chemically distinct β2-AR ligands according to differences in their ability to promote receptor endocytosis. These findings reveal a discrete principle for achieving cellular signalling specificity, based on endosome-mediated spatial encoding of intracellular second messenger production and ‘location aware’ downstream transcriptional control. |
format | Online Article Text |
id | pubmed-4232470 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
record_format | MEDLINE/PubMed |
spelling | pubmed-42324702015-06-01 Spatial encoding of cyclic AMP signalling specificity by GPCR endocytosis Tsvetanova, Nikoleta G. von Zastrow, Mark Nat Chem Biol Article G protein-coupled receptors (GPCRs) are well known to signal via cyclic AMP (cAMP) production at the plasma membrane, but it is now clear that various GPCRs also signal after internalization. Apart from its temporal impact through prolonging the cellular response, does the endosome-initiated signal encode any discrete spatial information? Using the beta2-adrenoceptor (β2-AR) as a model, we show that endocytosis is required for the full repertoire of downstream cAMP-dependent transcriptional control. Next, we describe an orthogonal optogenetic approach to definitively establish that the location of cAMP production is indeed the critical variable determining the transcriptional response. Finally, our results suggest that this spatial encoding scheme helps cells functionally discriminate chemically distinct β2-AR ligands according to differences in their ability to promote receptor endocytosis. These findings reveal a discrete principle for achieving cellular signalling specificity, based on endosome-mediated spatial encoding of intracellular second messenger production and ‘location aware’ downstream transcriptional control. 2014-11-02 2014-12 /pmc/articles/PMC4232470/ /pubmed/25362359 http://dx.doi.org/10.1038/nchembio.1665 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Tsvetanova, Nikoleta G. von Zastrow, Mark Spatial encoding of cyclic AMP signalling specificity by GPCR endocytosis |
title | Spatial encoding of cyclic AMP signalling specificity by GPCR endocytosis |
title_full | Spatial encoding of cyclic AMP signalling specificity by GPCR endocytosis |
title_fullStr | Spatial encoding of cyclic AMP signalling specificity by GPCR endocytosis |
title_full_unstemmed | Spatial encoding of cyclic AMP signalling specificity by GPCR endocytosis |
title_short | Spatial encoding of cyclic AMP signalling specificity by GPCR endocytosis |
title_sort | spatial encoding of cyclic amp signalling specificity by gpcr endocytosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4232470/ https://www.ncbi.nlm.nih.gov/pubmed/25362359 http://dx.doi.org/10.1038/nchembio.1665 |
work_keys_str_mv | AT tsvetanovanikoletag spatialencodingofcyclicampsignallingspecificitybygpcrendocytosis AT vonzastrowmark spatialencodingofcyclicampsignallingspecificitybygpcrendocytosis |